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J Biol Chem, Vol. 275, Issue 8, 5478-5484, February 25, 2000

Pairwise Electrostatic Interactions between alpha -Neurotoxins and gamma , delta , and epsilon  Subunits of the Nicotinic Acetylcholine Receptor*

Hitoshi OsakaDagger §, Siobhan MalanyDagger , Brian E. MollesDagger , Steven M. Sine||, and Palmer TaylorDagger

From the Dagger  Department of Pharmacology, University of California, San Diego, La Jolla, California 92093 and the || Receptor Biology Laboratory, Department of Physiology and Biophysics, Mayo Foundation, Rochester, Minnesota 55905

alpha -Neurotoxins bind with high affinity to alpha -gamma and alpha -delta subunit interfaces of the nicotinic acetylcholine receptor. Since this high affinity complex likely involves a van der Waals surface area of ~1200 Å2 and 25-35 residues on the receptor surface, analysis of side chains should delineate major interactions and the orientation of bound alpha -neurotoxin. Three distinct regions on the gamma  subunit, defined by Trp55, Leu119, Asp174, and Glu176, contribute to alpha -toxin affinity. Of six charge reversal mutations on the three loops of Naja mossambica mossambica alpha -toxin, Lys27 right-arrow Glu, Arg33 right-arrow Glu, and Arg36 right-arrow Glu in loop II reduce binding energy substantially, while mutations in loops I and III have little effect. Paired residues were analyzed by thermodynamic mutant cycles to delineate electrostatic linkages between the six alpha -toxin charge reversal mutations and three key residues on the gamma  subunit. Large coupling energies were found between Arg33 at the tip of loop II and gamma Leu119 (-5.7 kcal/mol) and between Lys27 and gamma Glu176 (-5.9 kcal/mol). gamma Trp55 couples strongly to both Arg33 and Lys27, whereas gamma Asp174 couples minimally to charged alpha -toxin residues. Arg36, despite strong energetic contributions, does not partner with any gamma  subunit residues, perhaps indicating its proximity to the alpha  subunit. By analyzing cationic, neutral and anionic residues in the mutant cycles, interactions at gamma 176 and gamma 119 can be distinguished from those at gamma 55.

* This work was supported by United States Public Health Service Grants GM 18360 (to P. T.) and NS 31744 (to S. M. S.), a Uehara Memorial Foundation fellowship (to H. O.), a California Tobacco Related Diseases fellowship (to S. M.), and United States Public Health Service Grant GM T32-07752 and an ASSERT fellowship (to B. E. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Current address: Dept. of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan.

The first two authors contributed equally to this work.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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